Magnetic resonance imaging (MRI) is an imaging technique used primarily in the medical field to produce high quality images of the inside of the human body. MRI's are based on a spectroscopic technique used to obtain microscopic chemical and physical information about molecules. MRI's started as a tomographic imagery technique that produced an image of the nuclear magnetic resonance signal in a thin slice through the human body. MRI's have advanced past tomographic imaging to a volume imaging technique.
Magnetic resonance imaging (MRI), uses a powerful magnetic field to align the nuclear magnetization of, for example hydrogen atoms in water in the body. Radiofrequency fields are used to systematically alter the alignment of this magnetization, causing the hydrogen nuclei to produce a rotating magnetic field detectable by the scanner. This signal can be manipulated by additional magnetic fields to build up enough information to construct an image of the body. When a patient goes inside the powerful magnetic field of the scanner these protons align with the direction of the field.
A second radiofrequency electromagnetic field is then briefly turned on causing the protons to absorb some of its energy. When this field is turned off the protons release this energy at a radiofrequency which can be detected by the scanner. The position of protons in the body can be determined by applying additional magnetic fields during the scan which allows an image of the body to be built up. These are created by turning gradients coils on and off which creates the familiar knocking sounds during an MR scan.
Diseased tissue, such as tumors, can be detected because the protons in different tissues return to their equilibrium state at different rates. By changing the parameters on the scanner this effect is used to create contrast between different types of body tissue. Contrast agents may be injected intravenously to enhance the appearance of blood vessels, tumors or inflammation. Contrast agents may also be directly injected into a joint, in the case of arthrograms, MR images of joints.
Image contrast is created by differences in the strength of the NMR signal recovered from different locations within the sample. This depends upon the relative density of excited nuclei (usually water protons), on differences in relaxation times (T1, T2 and T2*) of those nuclei after the pulse sequence, and often on other parameters.
Contrast in most MR images is actually a mixture of all these effects, but careful design of the imaging pulse sequence allows one contrast mechanism to be emphasized while the others are minimized. In some situations it is not possible to generate enough image contrast to adequately show the anatomy or pathology of interest by adjusting the imaging parameters alone, in which case a contrast agent may be administered. This can be as simple as water, taken orally, for imaging the stomach and small bowel. However, most contrast agents used in MRI are selected for their specific magnetic properties. Most commonly, a paramagnetic contrast agent (usually a gadolinium compound)
There have been concerns raised recently regarding the toxicity of gadolinium-based contrast agents and their impact on persons with impaired kidney function. The American College of Radiology released screening criteria for patients intended to be given Gadolinium-based contrast agents to identify potential risk factors for negative reactions. Special actions may be taken, such as hemodialysis following a contrast MRI scan for renally-impaired patients. More recently, superparamagnetic contrast agents (e.g. iron oxide nanoparticles) have become available. These agents appear very dark on T2*-weighted images and may be used for liver imaging, as normal liver tissue retains the agent, but abnormal areas (e.g. scars, tumors) do not. They can also be taken orally, to improve visualization of the gastrointestinal tract, and to prevent water in the gastrointestinal tract from obscuring other organs (e.g. pancreas). Diamagnetic agents such as barium sulfate have also been studied for potential use in the gastrointestinal tract, but are less frequently used.
Paramagnetic contrast agents have been demonstrated to provide clinical effectiveness in MRI's. The capacity to differentiate regions/tissues that may be magnetically similar but histologically distinct is a major impetus for the preparation of these agents. In the design of MRI agents, attention must be given to a variety of properties that will ultimately effect the physiological outcome apart from the ability to provide contrast enhancement. Two fundamental properties that must be considered are biocompatability and proton relaxation enhancement. Biocompatability is influenced by several factors including toxicity, stability (thermodynamic and kinetic), pharmacokinetics and biodistribution. Proton relaxation enhancement (or relaxivity) is chiefly governed by the choice of metal and rotational correlation times.
Paramagnetic metal ions, as a result of their unpaired electrons, act as potent relaxation enhancement agents. They decrease the T, and T2 relaxation times of nearby (independence) spins. Some paramagnetic ions decrease the T, without causing substantial linebroadening (e.g. gadolinium (III), (Gd3+)), while others induce drastic linebroadening (e.g. superparamagnetic iron oxide). The lanthanide atom, Gd3+, is by the far the most frequently chosen metal atom for MRI contrast agents because it has a very high magnetic moment (u1=63BM2), and a symmetric electronic ground state, (S8). Transition metals such as high spin Mn (II) and Fe (III) are also candidates due to their high magnetic moments. Once the appropriate metal has been selected, a suitable ligand or chelate must be found to render the complex nontoxic. A number of chelators have been used, including diethylenetriaminepentaacetic (DTPA), 1,4,7,10-tetraazacyclododecane′-N,N′N″,N′″-tetracetic acid (DOTA), and derivatives thereof. See WO/1999/025389, U.S. Pat. Nos. 5,155,215, 5,087,440, 5,219,553, 5,188,816, 4,885,363, 5,358,704, 5,262,532, and Meyer et al., Invest. Radiol. 25: S53 (1990).